Project Summary: Signal transduction via guanine nucleotide binding proteins (G proteins) is crucial in regulation of cardiovascular, neural, endocrine, and immune cell function as well as in cell growth and differentiation. It has been increasingly recognized that turning off cellular signals is as important as turning them on. This is evident in the function of the novel protein family, regulators of G protein signaling (RGS proteins). They are responsible for the subsecond turn-off of G protein regulated potassium channels in heart and strongly inhibit Gi and Gq signal transduction pathways. While much is known about the biochemistry of RGS proteins, little is known about their in vivo functions or their potential as targets of drug design. We have developed two mouse models in which Gi family G proteins are mutated to prevent RGS action (Gai2 and Goto G184S). The Gaj2G184S/G184S mouse shows dramatic alterations in cardiovascular, central nervous system, hematologic, and metabolic processes. In this proposal will ask "What are the roles of Ga subunits and RGS proteins in cardiovascular and metabolic function?" by use of these RGS insensitive G<Xj2 and Ga0 mouse models and RNAi-mediated suppression of RGS activity. Specifically, we will test role of RGS proteins in cardiac automaticity and ischemic injury. We will also examine RGS action and its effects on drugs controlling adipocyte function and glucose metabolism in vivo. These studies should permit a better understanding of the broad role of RGS proteins in the physiology of heart and adipose tissue and will evaluate the potential of RGS proteins as a novel target of drug action in cardioprotection, glucose homeostasis, and lipid metabolism. Relevance: Cardiovascular and metabolic diseases including diabetes and obesity are major killers in the United States. The pharmaceutical industry focuses on the limited range of therapeutic targets that they consider tractable. Our study will explore the function of a poorly understood but functionally important protein family involved in heart and fat tissue function. The ultimate goal is to define their potential as therapeutic targets in heart disease, obesity, and diabetes.